1. Meconium Aspiration Syndrome
Meconium-stained amniotic fluid is present in 5-20% of all births in the U.S. Each year, approximately 26,000 newborn infants in the U.S. develop Meconium Aspiration Syndrome (MAS) (Wiswell et al, Pediatr. Clin. North Am., 40:955-981, 1993; Gregory et al, J. Pediatrics, 85:848-852, 1974), involving progressive respiratory distress, hypoxia, hypercapnea, and acidosis requiring long-term ventilatory treatment. Severe cases require extracorporeal membrane oxygenation (ECMO) for survival (Bascik, Pediatr. Clin. North Am., 24:463-479, 1977; Moront et al, J. Thorac. Cardiovasc. Surg., 97:706-714, 1990; Toomasian et al, ASAID Trans., 34:140-147, 1988). Mortality rates vary between 4-12%. (See, e.g., Wiswell et al, Id., 1993; Coltar et al, Br. J. Obstet. Gynecol., 96:411-414, 1989; Davis et al, Am. J. Obstet. Gynecol., 151:731-736, 1985; Faleiglia, Obstet. Gynecol., 71:349-353, 1988).
Meconium aspiration can result in hypoxemia, vascular shunting and decreased compliance (Tyler et al, Pediatrics 62:454-459, 1978; Chen et al, Crit. Care. Med., 13:233-236, 1985). Experimental studies have shown that after inhalation of meconium, collapse of subpleural alveoli takes place (Nieman et al, J. Appl. Physiol., 58:129-136, 1985; Clark et al, Pediatr. Res., 13:532, 1979) and gross and microscopic atelectasis develops (Clark et al, J. Pediatr., 110:765-770, 1987; Sun et al, J. Appl. Physiol., 77:1961-1971, 1994; Sun et al, Acta Paediatr., 82:182-189, 1993; Sun et al, Biol. Neonate, 63:96-104, 1993; Seo et al, Pediatr. Pathol., 10:539-548, 1990).
Atelectasis may result from mechanical obstruction (Tyler et al, Pediatrics, 62:454-459, 1978; Gooding et al, Radiology, 100:131-135, 1971; Tran et al, Pediatr. Res., 14:34-38, 1980) caused by the particulate meconium, a so-called chemical pneumonitis and meconium-induced dysfunction of surfactant. While mechanical obstruction may play a role in meconium-induced pulmonary injury, the use of filtered meconium, obviating mechanical obstruction, led to loss of pulmonary function and alveolar collapse (Chen et al, Crit. Care. Med., 13:233-236, 1985). This indicated a direct effect in vivo of the meconium on surfactant in the lung tissue. Surfactant extracts of atelectatic lung taken after meconium aspiration revealed poor surface tension in the Wilhelmy balance assay compared to those taken from expanded lung (Clark et al, J. Pediatr. 110:765-770, 1987), and in studies of adult rats and piglets, surfactant removed by lavage 60 min. after meconium aspiration showed poor surface tension properties (Sun et al, Acta Paediatr., 82:182-189, 1993; Davey et al, Ped. Res., 16:101-108, 1993).
A direct action of meconium on surfactant has been shown in vitro. A dose-dependent loss of surface activity of surfactant was produced by human meconium (Davey et al, Id., 1993; Moses et al, Am J Obstet Gynecol., 164:477-481, 1991). Both chloroform and aqueous extracts of meconium have been found active (Sun et al, Acta Paediatr., 82:182-189, 1993; Moses et al, Am J Obstet Gynecol., 164:477-481, 1991), although in a separate study (Clark et al, J. Pediatr., 110:765-770, 1987), only the organic extract was stated to be active.
Constituents of meconium that may contribute to alteration of the physical properties of surfactant include fatty acids, cholesterol, bile salts, bilirubin, and proteolytic enzymes (Clark et al, J. Pediatr., 110:765-770, 1987; Sun et al, Acta Paediatr., 82:182-189, 1993; Moses et al, Am J Obstet Gynecol, 164:477-481, 1991; Henderson et al, Can. J. Surg., 18:64-69, 1975; Lieberman, Gastroenterology, 50:183-190, 1966).
Another factor in the development of pulmonary dysfunction has been stated to be a "chemical pneumonitis" (Gregory et al, J. Pediatrics, 85:848-852, 1974; Bascik, Pediatr. Clin. North Am., 24:463-479, 1977; Tyler et al, Pediatrics, 62:454-459, 1978). While this dysfunction has not been clearly defined, it is presumed to follow interaction of components of meconium and the lung tissues. It is also difficult to distinguish a "chemical pneumonitis" from the inflammatory reaction that is stimulated by meconium aspiration (Tyler et al, Pediatrics, 62:454-459, 1978; Sun et al, J. Appl. Physiol., 77:1961-1971, 1994; Davey et al, Ped. Res., 16:101-108, 1993). Such an inflammatory reaction is characterized by edema, leukocyte accumulation and hemorrhage, developing 2-5 hours after exposure of the lungs to meconium and, according to a single report, increasing in severity over a 48 hour period (Tyler et al, Pediatrics, 62:454-459, 1978).
The components of meconium that initiate the inflammatory response, and the molecular mediating systems involved are poorly understood. Further, the effect of the inflammatory response on pulmonary function has not been determined.
With the evidence that surfactant function is impaired by meconium aspiration, some efforts have been directed toward therapeutic intervention with exogenous surfactant. Auten et al. treated 14 neonatal infants--seven with MAS and seven with Respiratory Distress Syndrome (RDS) associated with pneumonia--with calf lung surfactant extract and observed some improvement in lung function, but only minimal clearing of chest radiographs (Auten et al, Pediatrics, 87:101-107, 1991). A majority of the patients required additional surfactant treatment. (Also see Davis et al, Pediatr. Pulmonol., 13:108-112, 1992).
Lotze et al. compared the response in 28 neonatal infants with MAS, pneumonia, hyaline membrane disease and idiopathic pulmonary hypertension of the newborn to four bolus doses of bovine surfactant, with 28 similar infants in a control group, who were treated with air alone (J. Pediatr., 122:261-268, 1993). All the infant patients in that study, including those receiving boluses of bovine surfactant, required ECMO, although the surfactant treatment was found to improve pulmonary mechanics and reduce time on ECMO. When the initial study was expanded to include 167 patients in the surfactant group and 161 patients in the air-placebo group, a decreased need for ECMO in the surfactant group was observed in a statistically significant manner, but only in those patients with the least severe disease. No difference was found in time on ventilation, oxygen requirements, time to discharge, or incidence of pneumothorax, pulmonary interstitial emphysema and chronic lung disease (Lotze, Ped. Research, 39:#4 226A, 1996).
In a separate study, bolus administration of bovine surfactant to full-term neonates with either severe MAS (n=20) or severe RDS (n=29) produced increases in a/A ratio and a fall in Oxygen Index over a 6 hour period (Khammash et al, Pediatrics, 92:135-139, 1993). Most of the infants in both groups required additional doses of the surfactant, however.
Results from studies addressing the efficacy of bolus surfactant treatment in animal models of MAS have been mixed. Sun et al. observed that intratracheal instillation of a slurry of human meconium in adult rats and newborn rabbits resulted in pulmonary injury that was diminished by bolus administration of porcine lung surfactant extract (Sun et al, J. Appl. Physiol., 77:1961-1971, 1994; Sun et al, Biol. Neonate, 63:96-104, 1993; Sun et al, Am. J. Crit. Care Med., 154:764-770, 1996). Similarly, Smith claimed that bolus administration of surfactant brought about an improvement in lung function in animal models of MAS. (See Smith et al, "Exogenous surfactant in the treatment of the meconium aspiration syndrome (MAS)," presented at the 9th Annual High Frequency Ventilation of the Newborn meeting, Snowbird, Utah, Apr. 2, 1992).
However, when Wiswell et al. studied two different surfactants in a piglet model of MAS, they failed to observe differences from controls in mean airway pressures and a/A ratio over a 6 hour period (Wiswell et al, Pediatrics Res, 36:494-500, 1994). Histologic observations were also similar in treated and control groups. Therefore, studies to date suggest that the results are equivocal when bovine- or porcine-derived surfactant preparations are administered, particularly when administered as a bolus.
In view of the variable and limited efficacy of bolus surfactant strategies in the treatment of MAS, attention has recently been focused on approaches employing pulmonary lavage. Limited studies using piglets or rabbits as MAS models, wherein the animals' meconium-injured lungs were treated with lavage solutions. The investigators claimed that lung function improved when surfactant was administered, but not when saline lavages alone were used (Paranka et al, Pediatr Res, 31:625-628, 1992; and Ohama et al, Acta Paediatr Japonica, 33:236-238, 1994). (See also Balaraman et al, Am. J. Respir. Crit. Care Med., 153:1838-1843, 1996). Similarly, two human infants with severe MAS, both destined for ECMO, were treated with repeated saline lavage, 10 ml/kg, followed by instillation of bovine surfactant. Both infants responded rapidly with an increase in a/A and clearing of chest radiographs in 4-5 hours (Ibara et al, Acta. Paed. Japonica, 37: 64-67, 1995).
2. Acute Respiratory Distress Syndrome (ARDS)
ARDS is an inflammatory disease of the lung, occurring in all ages of human beings, involving approximately 50,000-100,000 people in the United States per year. As the disease progresses, pulmonary function fails, requiring mechanical ventilation, and approximately 40-50% of patients die with the disease.
Many initiating factors lead to the development of ARDS, including aspiration of injurious substances such as gastric contents, inhalation of noxious fumes, including smoke or NO.sub.2, pneumonia, pulmonary contusion, trauma, multiple transfusions, burns, sepsis, pancreatitis, etc. The early disease is marked by an edematous response in the lung, with accumulation of neutrophils, leading to the development of chronicity in a week with fibrin deposits and collagen production. Injury to epithelial cells is observed in the early phase together with interstitial edema.
During the development of injury, intrinsic surfactant is degraded, losing function, and atelectatic collapse of the alveoli is prominent.
Complications are prominent: failure of peripheral organs, including kidneys, liver, gastrointestinal tract and the arterial system is common. Mortality rises in proportion to the number of systems undergoing failure. There is no specific therapy for this disease.
In view of the variability in efficacy achieved by using exogenous surfactants--particularly when the surfactant is derived from non-human sources or when the surfactant is given as a bolus--and in view of the somewhat equivocal results achieved when standard lavage methods are used, alternative therapeutic modalities and formulations are clearly needed. Therefore, the compositions and methods disclosed herein provide a very real improvement over therapies and compositions described in the art.